Recent estimates indicate that one in ten men and one in six women who live to 55 years will be diagnosed with Alzheimer's disease (AD). This disease, characterized by marked cognitive decline and neuropathology, leads to loss of independence and significant psychological and financial burdens for individuals, their families, and society. Early identification of AD is essential for improving disease outcomes as mid- and late-stage disease is accompanied by marked neuronal loss and other pathology which present significant barriers for effective treatments. Moreover, there is a current lack of behavioral assays that both identify AD early and that translate well between rodent models, from which the vast majority of the neurobiological data are derived, and humans, who suffer from the disease. The hippocampus is a brain structure that declines early and precipitously in AD, and tasks that assess hippocampal function are among the best targets for novel cognitive assessments. A unique aspect of hippocampal function only recently tested within the context of AD is based on evidence that this system plays an important role in the ability to apply previously learned information to novel problems and situations (referred to as 'transfer learning'). Transfer learning is impaired in humans with hippocampal damage and elderly individuals with mild hippocampal atrophy (but who still perform well on standard neuropsychological assessments). A small scale study has even shown that transfer learning deficits predict those individuals who will progress into AD over a 2 year window. Recently, we successfully developed a mouse analogue of this human task, and found that transfer learning is also sensitive to age-related AD- associated pathology in a widely-used mouse model of the disease. The overarching theme of the current proposal is to extend our understanding of transfer learning using our recently developed mouse transfer learning task, with the ultimate goal of both identifying early cognitive changes associated with AD pathology and halting the progression of neurobiological and cognitive deficits in a well-established mouse model of the disease. The data obtained from these studies should directly translate into novel avenues for the early detection of, and superior treatment strategies for, individuals with or at risk for developing AD. Aim 1 will evaluate the effects of bilateral hippocampal lesions on the transfer task, to determine whether the hippocampus is indeed critical for transfer learning. Aim 2 will expand upon our Preliminary Data and characterize performance on the transfer task in relation to performance on the water maze at multiple timepoints across the lifespan in a widely used mouse model of AD. In addition, Aim 2 will examine the relationship between transfer learning deficits in this mouse model and markers of synaptic integrity in hippocampus. Aim 3 will provide a foundation for using mouse transfer learning as a preclinical model for testing therapies for AD and determine if treatment regimens started at the onset of AD-like pathology can halt or reduce the progression of cognitive deficits in the AD mouse model. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is an age-related progressive neurodegenerative disorder characterized by a marked loss of memory and other cognitive functions. Work under the proposed experiments will build on exciting results from our lab and others related to a novel cognitive assay (i.e., transfer learning) that may have significant advantages over traditional assessments in that it appears sensitive to early detection of the disease and is highly translational across humans and transgenic mouse models, yielding improved comparative power across species. Results from these studies should directly translate into novel avenues for the early detection of Alzheimer's disease and superior preclinical testing of treatment strategies for individuals with or at risk for developing age-related cognitive decline.